Recent findings demonstrate that the TGF-beta receptor complex is a new addition to the family of human tumor suppressor genes and that inactivation of these receptors is important in multiple human malignancies. Because human cancer cells frequently demonstrate resistance to the normal growth inhibitory effects of TGF-beta, it has been proposed that the development of such TGF-beta resistance represents a significant step during carcinogenesis. We have demonstrated a strong correlation between the resistance to TGF-beta and gross structural abnormalities in the TGF-beta type II receptor (RII) gene in human gastric cancers. In addition, we have reported that mutation and transcriptional repression of the TGF-beta type II receptor correlated with the loss of responsiveness of tumor cell lines to TGF-beta. Transcriptional regulation of the TGF-beta RII gene. Several lines of evidence have suggested that the transcriptional repression of the TGF-beta RII gene may be important in modulating TGF-beta responsiveness. Our laboratory has cloned a novel transcription factor, ERT, that interacts with the purine rich sequences in the TGF-beta RII promoter region and regulates TGF-beta RII expression. Recent studies have implicated members of the ets family of transcription factors as pathogenic mechanisms for multiple malignancies. We previously have identified multiple Ets binding sites in the TGF-beta RII promoter, suggesting the functional importance of these sites in the transcriptional regulation of the RII gene. Ewing sarcoma (ES) specific chromosomal translocations fuse the EWS gene to a subset of the ets transcription factor family, the FLI1, ERG, or ETV1 gene. EWS-FLI1, EWS-EGR, and EWS-ETV1 are thought to act as aberrant transcription factors that bind DNA through their ETS DNA binding domains. We have shown that the EWS-Ets fusion proteins act as potent repressors of the TGF-beta type II receptor gene, and that introduction of normal TGF-beta RII into an ES cell line restores TGF-beta sensitivity and blocks tumorigenicity. These results indicate that the transcriptional repression of TGF-beta RII is a major target of the EWS-Ets. Our overall research over the past years has suggested that a pharmacologic augmentation of TGF-beta signaling pathways in human cancers such as stomach and Ewing's sarcomas may be a potential therapeutic strategy. Recently, we have demonstrated that a histone deacetylase inhibitor suppresses the proliferation of human breast cancer cells and specifically enhances TGF-beta signaling by increasing the level of expression of TGF-beta type II receptor.